Constrained Intracellular Survival ofMycobacterium tuberculosisin Human Dendritic Cells

Abstract

Dendritic cells (DCs) are likely to play a key role in immunity against Mycobacterium tuberculosis, but the fate of the bacterium in these cells is still unknown. Here we report that, unlike macrophages (Mφs), human monocyte-derived DCs are not permissive for the growth of virulent M. tuberculosis H37Rv. Mycobacterial vacuoles are neither acidic nor fused with host cell lysosomes in DCs, in a mode similar to that seen in mycobacterial infection of Mφs. However, uptake of the fluid phase marker dextran, and of transferrin, as well as accumulation of the recycling endosome-specific small GTPase Rab11 onto the mycobacterial phagosome, are almost abolished in infected DCs, but not in Mφs. Moreover, communication between mycobacterial phagosomes and the host-cell biosynthetic pathway is impaired, given that <10% of M. tuberculosis vacuoles in DCs stained for the endoplasmic reticulum-specific proteins Grp78/BiP and calnexin. This correlates with the absence of the fusion factor N-ethylmaleimide-sensitive factor onto the vacuolar membrane in this cell type. Trafficking between the vacuoles and the host cell recycling and biosynthetic pathways is strikingly reduced in DCs, which is likely to impair access of intracellular mycobacteria to essential nutrients and may thus explain the absence of mycobacterial growth in this cell type. This unique location of M. tuberculosis in DCs is compatible with their T lymphocyte-stimulating functions, because M. tuberculosis-infected DCs have the ability to specifically induce cytokine production by autologous T lymphocytes from presensitized individuals. DCs have evolved unique subcellular trafficking mechanisms to achieve their Ag-presenting functions when infected by intracellular mycobacteria.

Deciphering the genetic architecture of variation in the immune response toMycobacterium tuberculosisinfection

“…Changes in the transcriptome following MTB infection are expected to reflect the transition of DCs from antigen-capturing cells to potent antigen-presenting cells and T-cell activators (19,20). Consistent with this notion, we found that the maturation of DCs after MTB infection was accompanied by the strong upregulation of genes involved in immune responses (FDR < 10 −26 ), including cytokine signaling, T-cell activation, and antigen presentation (FDR < 0.006; Fig.…”

“…1B and Dataset S2). This observation probably reflects a reduced capacity of mature DCs to endocytose/phagocytose and the expected reduction in trafficking between the mycobacterial phagosome and the host cell recycling and biosynthetic pathways (20,21).…”

The innate immune response in human tuberculosis

“…Mtb is capable of replicating within DCs (Förtsch et al ., 2000), and some reports show that Mtb actually manipulates DC function and impairs their ability to control infection (Hanekom et al ., 2003). However, other studies find that DCs are beneficial to bolster the cellular immune response (Tailleux et al ., 2003). …”

Alteraciones en el reclutamiento y activación de proteínas Rab durante la infección micobacteriana

“…Luego de 5 días de infección, 45% a 65% de los fagosomas micobacterianos retuvieron la expresión de esta GTPasa; este hallazgo se ha asociado con acceso de los compartimentos a la vía de reciclaje y a nutrientes (expresión de transferrina), y se ha encontrado que estos fagosomas tienen además acceso a la vía biosintética (expresión de proteínas específicas del RE, calnexina y Grp78/BiP) y comunicación con la vía endocítica (mediante la adquisición de dextrán). Asimismo, estos macrófagos son permisivos para la replicación micobacteriana (91).…”